Pre-doctoral Fellowship Grant Awarded to Reyes Hernández Osuna

The immune system plays a crucial role in the anti-tumor response. Despite the encouraging clinical results obtained in other types of tumors, the particular immunological environment of the diffuse intrinsic pontine glioma (DIPG) has hindered the use of this approach as an efficacious alternative to the current treatment of DIPG. Even so, our group has demonstrated the feasibility of using oncolytic viruses, a type of bioimmunotherapy, at different levels of this disease.

As we have shown, the preclinical administration of the oncolytic adenovirus Delta-24-ACT (with the capacity to awake the patients’ immune system) in DIPG is safe, but its efficacy can be further enhanced. Incorporating additional transgenes to Delta-24-ACT can be a feasible strategy to achieve a sustained in situ delivery of additional molecules, potentiating the effect of oncolytic virotherapy while overcoming the risk of exacerbating systemic toxicity. On the other hand, preliminary data from our lab indicates that the expression of TIM-3 in the tumor microenvironment (TME), specifically in the myeloid compartment, could pose a resistant mechanism to anti-DIPG therapies. Moreover, we have demonstrated that TIM-3 is a potential therapeutic target in DIPG and that its blockade mediates potent anti-tumor responses in DIPG mouse models.

Here we propose to develop the Delta-24-ACT virus encoding a TIM-3 inhibitory molecule as a comprehensive approach against DIPG, invigorating innate and adaptive arms of the anti-tumor immune response in a single treatment. The dual anti-tumor effect of this virus (oncolysis and immunostimulation) will be assessed in relevant murine and humanized DIPG models. If successful at the end of this project, we will be in the position to propel a phase I/II clinical trial with this new oncolytic virus: Delta-24-DMG-ACT.